Moderate to severe Restless Legs Syndrome (RLS) is a major public health problem, significantly affecting 1.5 to 3% of adult Americans (3 - 7 million), resulting in profound sleep loss and an urge to move during sitting or resting in the latr part of the day. Work productivity is decreased by 20%, quality of life is as bad as or worse than that for other chronic diseases, e.g. arthritis and diabetes, and there is increased cardio- vascular disease risk. Current approved dopaminergic treatments fail to improve sleep time, engender impulsive behaviors and may make RLS worse. New treatments and new research directions to find them are needed. The current research focus on the sensory features has failed to address an important aspect of RLS; i.e. a 'hyperarousal' or profound chronic sleep loss without significant excessive daytime sleepiness. This hyperarousal produces RLS symptoms by overwhelming the normal inhibitory processes needed to decrease sensory and motor cortical activity for resting and sleep. Thus the hyperarousal produces both the RLS need to move when trying to rest and the inability to maintain sleep. The biological consequences of this hyperarousal process on sleep (increased wake time) and cortical excitability (as demonstrated by transcranial magnetic stimulation (TMS)) are postulated to reflect increased degree of excitatory glutamatergic activity, and therefore affected brain regions will show relatively increased glutamate (Glu) and glutamine (Gln) on MR spectroscopy (MRS). Changes in inhibitory activity and GABA may also occur, but less significantly than the increase in Glu/Gln. Our pilot MRS data discovered a new abnormality in RLS: increased Thalamic Glx (Glu + Gln) that correlated well with sleep measures of hyperarousal. Glx levels are not specific for the neurotransmitter role of Glu. In this project RLS and matching controls subjects will be studied using polysomnograms (PSG) and TMS and 7T MRI for MRS that provides accurate measurement of Gln levels, which reflect mostly neurotransmitter Glu activity. The first aim is to confirm that Gln is increased in the thalamus and to determine if this also occurs in the motor and sensory cortices. The relation between Glu, Gln and GABA will also be evaluated. Second, assessments will be made of the degree of relation between Gln increase and the hyperarousal effects on sleep and cortical excitability (TMS). This would demonstrate that abnormally increased Glu activity is primary to RLS hyperarousal and radically changes the emphasis in RLS to be less on dopamine and more on Glu- hyperarousal as a major feature of RLS. This is an entirely new direction for RLS research and treatment development. The new concept of hyperarousal adds a missing dimension to understanding RLS, namely the discovery of the Glu abnormality and its central relation to the other hyperarousal features. It opens the opportunity to develop new animal and cell RLS research. It provides new directions for medication treatment development, changes the emphasis for primary treatment toward Glu drugs and the MRS provides a useful and accessible measure for evaluating medication treatment benefits. PUBLIC HEALTH RELEVANCE: Moderate to severe Restless Legs Syndrome (RLS) is a major public health problem, significantly affecting up to 3% of adult Americans (7 million), resulting in inability to rest or sleep (sleeping 3 - 5 hours every night), decreased quality of lie, and 20% loss of work productivity and increased risk of cardiovascular disease. The brain arousal systems appear to be overactive in RLS and would therefore be expected to produce neurochemical changes marking the disease status. This project includes measuring these neurochemicals in RLS with advanced magnetic resonance imaging, evaluating their relation to RLS symptoms and changing RLS treatment focus to new options aimed at correcting the overactive arousal process in RLS.